P1104: THE PROGNOSTIC ROLE OF DEPTH OF RESPONSE DEPENDS ON THE TIME OF ASSESSMENT AFTER FIRST-LINE IMMUNOCHEMOTHERAPY IN PATIENTS WITH SYMPTOMATIC WALDENSTROM MACROGOBULINEMIA (WM).
Authors: Lydia Montes, Caroline Delette, Daniela Robu, Delphine Lebon, Etienne Paubelle, Jean Pierre Marolleau, Pierre Morel
Journal: HemaSphere (2023)

Topic: 18. Indolent and mantle-cell non-Hodgkin lymphoma - Clinical Background: The current criteria for the assessment of response after treatment of patients with symptomatic WM (sWM) have been proposed following the 6th International Workshop on WM with the main aim to promote uniform reporting of clinical trial data but also to retain a predictive role for subsequent outcome. This guideline recommended to take into account the deepeest response observed during follow-up (Owen, BJH 2013, 160; 171). On one hand, attainment of complete/very good partial response (VGPR) following immunochemotherapy as first-line or salvage therapy has been shown to be an important determinant to progression-free survival (PFS) (Treon BJH 2011). On the other hand, time-dependent models failed to identify significant prognostic value for survival after first treatment intiaition associated with any level of response (Guidez, Blood Adv 2018 2; 3102). Aims: In order to understand both results and thus to explore the relationship between response and PFS, we assessed the changes in the linear predictor (LP) (and consequently hazard ratio [HR]) associated with partial response (PR) in Cox models of subsequent PFS and survival performed at 72 landmark points (every 2 weeks for the first 3 years after treatment initiation). Methods: Dynamic landmarking was performed according to van Houwelingen and Putter (Lifetime Data Anal 2008 14: 447). For this purpose, we updated the records of 128 symptomatic patients who received chemotherapy (CT 68 patients) or immunochemotherapy (ICT, 60 patients) as front line therapy (median age: 69 Interquartile range: 61-78, M/F=1.85, median PFS and survival after treatment intiation: 31 months; 95% confidence interval [95CI]: 36-44 and 108 months 95CI: 83-155, respectively). No patient received maintenance therapy. PR was recorded in 60 patients (after CT: 21; after ICT: 39) and VGPR in 10 patients (after CT: 3; after ICT: 7). Results: Using sandwich estimators to take into account the clustering of the data, significant favorable effect of PR achievement for subsequent PFS was only observed from the 8th to the 20th landmark points i;e. between 4 and 10 months and only in patients treated with ICT. No significant effet of PR on subsequent survival was observed at any landmark point. More importantly, a regression analysis showed a significant change in the LP with the landmark point rank in patients treated with CT (p<0.0001for subsequent PFS and survival) and ICT (p<0.0001for subsequent PFS and survival). Finally, we confirmed that achieving PR, coded as a time dependent covariate over the whole period of follow-up after first treatment initiation had no prognostic value (p=0.09). Summary/Conclusion: Overall, our findings highlight the importance of the timing of response assessment in WM: They confirmed the prognostic value of response after ICT frontline, for subsequent PFS, when assessed 4 to 10 months after treatment intiation (the usual time of completion of ICT). Conversely response status may retain less prognostic value outside of these timepoints. The change in the prognostic importance of response during the evolution likely explain the absence of prognostic value of response coded as a time dependent covariate. Thus, landmark and time-dependent analyses provide complementary information. Similar analyses should confirm the prognostic value of PR achievement at 6 months in patients wo received ibrutinib frontline or later (Castillo BJH 2021, 192, 542–550).Keywords: Waldenstrom’s macroglobulinemia